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Nat Immunol. 2020 Mar;21(3):274-286. doi: 10.1038/s41590-020-0593-9. Epub 2020 Feb 17.

HIV-1-induced cytokines deplete homeostatic innate lymphoid cells and expand TCF7-dependent memory NK cells.

Author information

1
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
2
Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA, USA.
3
Barrier Immunity Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
4
Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA.
5
Department of Medicine, University of California, San Francisco, CA, USA.
6
Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
7
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA. jeremy.luban@umassmed.edu.
8
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA. jeremy.luban@umassmed.edu.

Abstract

Human immunodeficiency virus 1 (HIV-1) infection is associated with heightened inflammation and excess risk of cardiovascular disease, cancer and other complications. These pathologies persist despite antiretroviral therapy. In two independent cohorts, we found that innate lymphoid cells (ILCs) were depleted in the blood and gut of people with HIV-1, even with effective antiretroviral therapy. ILC depletion was associated with neutrophil infiltration of the gut lamina propria, type 1 interferon activation, increased microbial translocation and natural killer (NK) cell skewing towards an inflammatory state, with chromatin structure and phenotype typical of WNT transcription factor TCF7-dependent memory T cells. Cytokines that are elevated during acute HIV-1 infection reproduced the ILC and NK cell abnormalities ex vivo. These results show that inflammatory cytokines associated with HIV-1 infection irreversibly disrupt ILCs. This results in loss of gut epithelial integrity, microbial translocation and memory NK cells with heightened inflammatory potential, and explains the chronic inflammation in people with HIV-1.

PMID:
32066947
PMCID:
PMC7044076
[Available on 2020-08-17]
DOI:
10.1038/s41590-020-0593-9

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